DE3214082A1 - NEW DERIVATIVES OF PHENYL ALIPHATIC CARBONIC ACIDS, THEIR PRODUCTION, THEIR USE AS MEDICINAL PRODUCTS AND THE COMPOSITIONS CONTAINING THEM - Google Patents

Description

ROUSSEL - UCLAF Paris / France

New derivatives of phenyl-aliphatic carboxylic acids, their Manufacture, their use as medicaments and the compositions containing them.

description

The present invention relates to new derivatives of phenylaliphatic Carboxylic acids, a process for their preparation and their use as medicaments and those containing them Compositions.

The present invention relates to the products of general formula I.

COOR (I)

wherein the three methoxy radicals in 3,4,5- or 2,4,6- or 2,4,5- or 2,3,5- or 2,3,6-position, in which either A and B together represent a double bond or A represents a hydrogen atom and B represents a hydroxyl group and wherein R is a hydrogen atom or an alkyl radical with 1 to 5 carbon atoms, in the various possible stereoisomeric forms as well as the alkali, alkaline earth or Amine salts of the products of the formula I in which R is a hydrogen atom.

The term alkyl of 1 to 5 carbon atoms can e.g.

" ^{:: ::} ..:". ^: L..X- "s 32 U 08

Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, Designate tert-butyl or pentyl radical.

The various possible stereoisomeric forms represent the products of the formula I in which A and B together have one Represent double bond, the geometric isomers E and Z (trans and cis) and for the products of formula I, wherein A represents a hydrogen atom and B represents a hydroxy radical, the various racemic and optically active forms of these Products.

The alkali or alkaline earth salts of the products of the formula I, in which R is a hydrogen atom, can, for example be the sodium, potassium, lithium or calcium salts.

The amine salts of the products of the formula I in which R is a hydrogen atom are the salts of conventional amines. Under usual Amines can be the monoalkylamines, such as methylamine, ethylamine, propylamine, the dialkylamines, such as dimethylamine, Diethylamine, di-n-propylamine, the trialkylamines like Call triethylamine. One can also mention piperidine, morpholine, piperazine and pyrrolidine.

The invention relates in particular to:

The products of the above formula I, in which A and B together represent a double bond, in the form of the E or Z isomers and the alkali, alkaline earth or amine salts of these products of the formula I, in which R is a hydrogen atom,

the products of the above formula I, in which A and B together represent a double bond, in the form of the E isomers and the alkali, alkaline earth or amine salts of these products of the formula I, in which R is a hydrogen atom,

the products of the above formula I, in which the three methoxy radicals are in the 3,4,5- or 2,4,5-position, in the form of the Ε isomers, as well as the alkali, alkaline earth or amine salts of these products of the formula I, in which R is a hydrogen atom.

" ^{:: ::} ..f: L.xO 32H082

Among the products according to the invention one can in particular to name:

the (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid and the (E) -4- (2,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid.

According to the invention, the products of the above formula I in the various possible stereoisomeric forms as well the alkali, alkaline earth or amine salts of these products of the formula I, in which R is a hydrogen atom, with the aid of a Process are prepared, which is characterized in that the glyoxylic acid or one of its alkyl esters Formula II

QHC-COOR (II)

wherein R denotes a hydrogen atom or an alkyl radical having 1 to 5 carbon atoms, with an acetophenone of the formula III

(in)

in which the methoxy radicals are in the positions indicated above, to form a product of the formula I _A corresponding to a product of the formula I in which A is a hydrogen atom and B is a hydroxyl group, or a product of the formula I ₁₃ corresponding to a product of the formula I. , wherein A and B together form a double bond with (E) -configuration, and optionally subjecting a product of the formula to a dehydrating agent to give a corresponding

Get product of formula I _D with (E) configuration and gets

If desired, a product of the formula I _{A obtained} splits into its optically active isomers and, if desired, a compound of the formula I _ß with (E) configuration isomerized into a compound of the formula I _ß with (Z) configuration and, if desired, a product of the formula I obtained , where R is a hydrogen atom, converted into a salt or esterified by customary methods.

32U082

By condensing a product of the formula II and a product of the formula III, depending on the working conditions, in particular the pH, the temperature, the heating time _, a product of the formula Ij is obtained. or a product of the formula I_ or a mixture of these products.

According to various possible combinations of the pH ,, the Temperature and duration of heating well known to those skilled in the art of this aldol condensation chemistry, one obtains more or less large proportions of product I or product I ".

The products of the formula I always form first and the products of the formula I derive therefrom by dehydration away.

In general, the proportion of product of the formula I which is formed directly increases when the working conditions are such that the milieu is more acidic (see e.g. MATHIEU and ALLAIS, Cahiers de Synthesis Organique, Volume 3, P. 102, the passage concerning the aldol condensation).

According to preferred conditions for carrying out the invention Procedure, the procedure described above is carried out in the following way:

a) one would like to obtain a product of the formula I_ directly, leads

15th

the reaction of the product of the formula II and the product of the formula III is carried out in a strongly acidic medium. The acidic environment can, for example, by an excess of glyoxylic acid or by the presence of an acid such as hydrochloric acid, Sulfuric acid, phosphoric acid or by adding sodium hydrogen sulfonate to the reaction medium.

For the direct preparation of the products I_, one can proceed in such a way that, for example, in the presence of acetic anhydride at 130 ⁰ C according to a process analogous to that in the am

Japanese patent application published October 3, 1977

: "-. f; L ..; ^: " * "* · 32U082

77 39 020 (C-A 88, 37442 p) or J.Med.Chem. 1972, volume _15_, No. 9, 918-22 described works. The glyoxylic acid can even optionally in the form of the alkali salt such as sodium or Potassium salt can be used.

If one would like to obtain products of the formula I ₁₃ , one preferably leads

Jd

perform the condensation of the product of the formula II and the product of the formula III at a temperature between 120 and 150 ^° C. and preferably the mixture is heated for more than 3 hours.

It is well known that the "aldols" dehydrate themselves very easily into the corresponding unsaturated derivatives, either by heating, or by treatment in an acidic medium _/ and that this dehydration either takes a few minutes at a high temperature, such as in the US PS 3,953,463 described (one to two minutes at 155 ° C) or at a lower temperature for a long period of time.

b) If the products of the formula I are to be obtained, the condensation of the product of the formula II with the product of the formula III is preferably carried out at a pH> 6. This condensation is preferably effected at a temperature of less than 100 ^° C. and in particular by heating for less than 3 hours.

If the product of the formula II, in which R is a hydrogen atom, is used, it can also advantageously be used at room temperature operate in the presence of a catalyst such as an alkaline agent (sodium hydroxide), e.g. potassium hydroxide.

c) The condensation of the product of the formula II and the product of the formula III can be carried out in a solvent or in the presence a solvent such as an aromatic or aliphatic hydrocarbon (benzene, toluene, heptane e.g.) will.

d) The eventual dehydration of a product of formula I ₇ . into a product of the formula I_ can, for example, by treatment in the

- Q _

Heat can be brought about in an acidic environment.

Suitable dehydrating agents include, for example, hydrochloric acid, Sulfuric acid, phosphoric acid or an alkali hydrogen sulfonate such as sodium or potassium hydrogen sulfonate.

e) The cleavage of the racemic products of the formula I into optically active isomers is effected by customary methods.

f) The alkali, alkaline earth or amine salts of the products of the formula I can be prepared by a customary process, such as, for example, by allowing these products of the formula I to act with appropriate bases or by double decomposition reaction or by any conventional method known for this type of oc, ε-ethylenic carboxylic acids.

The salt formation reaction is preferably carried out in a solvent or in a mixture of solvents such as water, ethyl ether, acetone, ethyl acetate, tetrahydrofuran or dioxane causes.

g) The products of the formula I in which R is an alkyl radical having 1 to 5 carbon atoms can be prepared starting from of products of the formula I in which R is a hydrogen atom means in the usual way by reaction with an alcohol of the formula ROH, preferably in an acidic medium. The acid can be, for example, hydrochloric acid, phosphoric acid, or p-toluenesulfonic acid be.

h) The products of the formula I in which A and B together represent a double bond, in the form of the Z isomers, can be obtained by Irradiation of the corresponding products of the formula I in the form of the Ε-isomers according to the method described in J.Org.Chem. rs, 1948 p. 284 Method can be obtained.

The products of the above formula I in the various possible stereoisomeric forms as well as the alkali, alkaline earth or Amine salts of these products of the formula I, in which R is a water

XV 32Τ4082

- 10 -

substance atom means possess interesting pharmacological Properties: In particular, they show significant antiulcer activity. moreover, when brought into contact with the gastric mucosa, they show gastric antisecretory activity and a cytoprotective effect.

These properties justify their use in therapy and the invention also relates to the products as medicaments of the formula I as defined above in the various possible stereoisomeric forms and the pharmaceutically acceptable forms Alkali, alkaline earth or amine salts of these products of the formula I, in which R is a hydrogen atom.

The invention relates in particular as a medicament: (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid and (E) -4- (2,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid.

All of the products defined above represent, according to the invention, very useful medicaments in human hepaper, especially in the treatment of hyperchlorhydria, Gastric ulcer, gastroduodenal ulcer, gastrites, hiatal hernia, and gastric and gastroduodenal diseases, accompanied by gastric hyperacidity.

The posology, which can be varied according to the product used and the respective disease, can, for example, vary between 0.05 and 2 g per day when administered orally to the adult extend.

The present invention also relates to pharmaceutical compositions containing as active ingredient at least one of the above Contain medicinal products. These compositions are made to be digestive or digestive can be administered by the parenteral route.

They can be solid or liquid and usually in the

- 11 -

Pharmaceutical forms used in human medicine are present, such as, for example, in the form of simple or sugar-coated tablets, gel capsules, granules, suppositories and injectable preparations. They are made using the usual methods.

The one or more 'active compounds can in this case usually used in such pharmaceutical compositions excipients used incorporated are such as talc, gum arabic, lactose animal _r starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances or vegetable origin, paraffin derivatives, glycols, various wetting agents, Dispersants or emulsifiers and preservatives.

The products of the formula II and III are known products.

The following examples illustrate the invention.

Example 1t 4- (2,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid.

19.3 g of glyoxylic acid, 50% by weight in water, are heated under reduced pressure until about 80% of the water present is removed and, after cooling, 14.6 g of 2,4,5-trimethoxyacetophenone are introduced into the reaction medium . The mixture is heated for 3 hours to 90 ^° C. under reduced pressure (<50 mm Hg), with any remaining water being distilled off at the same time.

After the medium has cooled down, the following is introduced: 200 cm ^{3 of} toluene

400 cm ^{3 of} water containing 7.5 g of sodium carbonate.

It is decanted, the aqueous phase is washed with toluene and then acidified to pH 1 with half-concentrated hydrochloric acid. The desired product is then extracted with ethyl acetate. After removal of the solvent and crystallization in 200 cm ^{3 of} 1,2-dichloroethane, 24.6 g of 4- (2,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid are obtained. F = 146 ⁰ C + 1 ° C.

-. : ΐ: _ Γ:!.; .. * ■ '■' ■ ' 32H082 - 12 -

Analysis: C. 54 , 93 H 5 / 67 Calculated: 54 / 9 5 , 7 Found :

NMR spectrum : Consistent with structure.

Acidimetry; (expressed as a percentage of theory): 100.5 + 0.5.

Example 2: (E) -4- (2,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid

11 g of 4- (2,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid, which was obtained in Example 1, 30 cm ^{3 of} acetic acid and 2 cm ^{3 of} concentrated hydrochloric acid (d = 1.18) are heated for 2 hours 30 minutes ) to reflux.

The solution obtained is then cooled to room temperature and then, after the addition of 100 cm ^{3 of} water, the precipitate formed is filtered off to give 7 g of the expected product in crude form. F = 207 - 208 ⁰ C.

After recrystallization in 20 cm ^{3 of} acetic acid, 6.3 g are obtained

of the expected product in pure form. F = 210 ⁰ C.

Analysis;

Calculated: C 58.64 H 5.30%
Found: 58.6 5.3%

NMR spectrum: the coupling constant of the vinyl protons is 16 Hz, which indicates a transisomerism.

Example 3: 4- (3,4,5-Trimethoxyphenyl) ^ -oxo ^ -hydroxybutanoic acid

29.6 g of glyoxylic acid _/ 50% in water are heated _; under reduced pressure until 80% of the water present has been removed and then, after cooling, introduces 84.1 g of 3,4,5-trimethoxyacetophenone into the reaction medium. The mixture is heated for 2 hours to 95 to 100 ⁰ C under reduced pressure (= * 50 mm Hg), with

. - 13 -

any remaining water present is distilled off at the same time.

After the medium has cooled, 120 cm ^{3 of} water containing 11.6 g of sodium carbonate and ether are introduced, decanted, the aqueous phase is washed with ether, and the aqueous phase is then acidified to pH 1 with half-concentrated hydrochloric acid.

The desired product is extracted with ethyl acetate. After removal of the extraction solvent and recrystallization from 1,2-dichloroethane, 31.5 g of the expected product are obtained. F = 119 - 120 ⁰ C.

Analysis;

Calculated: C 54.93 H 5.67%
Found: 54.9 5.7%

Acidimetry: (expressed as a percentage of theory): 98.3%.

Example 4: (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid

15.8 g of 4- (3,4,5-trimethoxyphenyl) -4-oxo-2-hydroxybutanoic acid, which was obtained in Example 3, 20 cm ^{3 of} acetic acid and 20 cm ^{3 of} concentrated hydrochloric acid are heated for 2 hours 30 minutes = 1.18) to reflux.

The reaction medium is cooled and precipitated with water.

The precipitate formed is filtered off. 12 g of the expected product are obtained in crude form. F = 140 ⁰ C.

After recrystallization from 40 cm ^{3 of} an ethanol-water mixture (1: 1), 10.5 g of the expected product are obtained in pure form. F = 144 ⁰ C.

Analysis:

Calculated: C 58.64 H 5.30%
Found: 58.4 5.3%

• j: - ".: ι!.: .. Χ '/ * 32H082

Acidimetry: (expressed in percent of theory): 98.7 + 0.5%

NMR spectrum: the coupling constant of the vinyl protons is 16 Hz, which indicates a transisomerism.

Example 5; (E) -4- (2,4,6-trimethoxyphenyl) -4-oxo-2-butenoic acid

Mixing 3.3 g Kaiiumhydroxid in cookie mold in 100 cm ³ of absolute ethanol, bringing it, 31.5 g of 2,4,6-trimethoxyacetophenone and then dropwise during 30 minutes at 2O ⁰ C a solution of 4.6 g of glyoxylic acid to 80% in water, in 50 cm ^{3 of} absolute ethanol.

The resulting solution is then refluxed for 6 hours and then evaporated to dryness under reduced pressure. The residue is taken up in 300 cm ^{3 of} water, filtered and the filtrate is collected and acidified to pH 1 with concentrated hydrochloric acid. The desired product crystallizes, it is filtered off with suction and then dried ^{to constant weight at 60 °} C. under reduced pressure. 0.7 g of the expected product is obtained and is recrystallized from methyl ethyl ketone. F = 152 ± 1 ° C.

Analysis: C, I3 ^H 1 4 ° 6 (266 .30) 5, 30th % Calculated: C. 58 , 64 H 5, 5 % Found : 58 , 7

NMR spectrum: the coupling constant of the vinyl protons is 16 Hz, which indicates a transisomerism.

Example 6: (E) -4- (3,4,5-Trimethoxyphenyl) ^ -oxo ^ -butenoic acid methyl ester .

A mixture of 20 g of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid, 150 cm ^{3 of} methanol and 0.15 g of p-toluenesulfonic acid is heated to reflux for 5 hours. The solution obtained is cooled to room temperature, 0.2 g of sodium acetate is added and the mixture is evaporated under reduced pressure. 200 cm ^{3 of} toluene are added to the residue, washed with an aqueous sodium bicarbonate

- 15 -

solution and then with water. The solvent is removed
under reduced pressure, the residue recrystallizes from a methanol / water mixture (1: 1) and 10.7 g of the desired product are obtained. F = 94 ⁰ C.

Example 7: Morpholine salt of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid.

It is poured 50 cm ^{3 of} ethyl ether containing 1.758 g of morpholine in
a solution containing 5.375 g of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid. The precipitate formed is filtered off, washed with ethyl ether and dried under reduced pressure. 6.5 g of the desired product are obtained. F = 140 ⁰ C.

Example 8; Sodium salt of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid.

At 10 ^° C., 28 cm ^{3 of} a 1N aqueous sodium hydroxide solution are added to a mixture of 7.7 g of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid and 30 cm ^{3 of} water. It is filtered and evaporated under reduced pressure. The solid obtained is taken up in acetone, filtered, washed with acetone and dried under
reduced pressure at 20 ^° C. 7 g of the desired are obtained
Product. F = 250 ⁰ C.

Example 9; Piperidine salt of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid

50 cm ^{3 of} ethyl ether containing 1.988 g of piperidine are added
a solution of 6.215 g of (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-buienic acid in 1200 cm ^{3 of} ethyl ether. The precipitate formed is filtered off, washed with ethyl ether and dried under reduced pressure. 7.3 g of the desired product are obtained in this way. F = 124 ° C.

Pharmaceutical Forms Example 10: Tablets
Tablets were made with the following formulation:

- 16 -

(E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid 100 mg Excipient quantum satis for a tablet with a final weight of 300 mg

(Components of the excipient: lactose, corn starch, treated Starch, rice starch, magnesium stearate, talc).

Example 11; Gelcaps

Gel capsules of the following formulation were made:

(E) -4- (2,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid 100 mg excipient quantum satis for a gel capsule with a Final weight of 300 mg

(Components of the excipient: talc, magnesium stearate, aerosil).

Pharmacological examination

1. Determination of the antiulcer activity of the products of Examples 1 to 4.

The technique used is described by SHAY et al in Gastroenterology, i>, 43, (1945). ,

SHAY's technique consists in inducing gastric ulcers in rats by pyloric ligature.

The animals are anesthetized with ether. One leads a longitudinal Incision about 1 cm below the sternum, exposes and brings the glandular part of the stomach and the duodenum a ligature a few millimeters below the pylorus. The muscle level is left as such and the skin is with two brackets in parentheses.

Animals receive immediately the dispersion medium or to substance under investigation by buccal route in a volume of 0.5 cm ^3/100 g and without food or drink to killing by karotidisches bleeding to death, which occurs approximately 16 hours after the treatment left.

I ". '32H082

- 17 -

Before the stomach is removed, a ligature is made above the cardia.

The gastric fluid is collected to measure the pH.

The stomach is then opened along the great curve, rinsed in physiological serum and spread on a graph paper for examination under a binocular magnifying glass tet.

The severity of the lesions is determined macroscopically and is rated from 0 to 4 for each stomach.

The average ulceration intensity is determined for each group of rats and the protection calculated by adding the mean index of the group is set in relation to the mean index of the comparison group.

The pH values of the gastric fluid are also determined for the animals examined and the comparison animals.

The following results are obtained:

Product of - dose gastric fluid pH Comparison Ulceration example (mg / kg) treated animals % Protection in ver animals relationship to the 2.3 Compare 1 100 2.5 3.2 43 2 20th 4.6 3.2 100 4th 3.6 2.7 72 3 100 3.7 1.8 45 4th 20th 2.4 1.2 98 4th 3.0 2.3 65 0.8 1.8 38

2) Determination of the antiulcer activity of the products of Examples 7 and 8.

The technique used is described by SHAY et al in Gastroenterology,

- 18 -

5_, 43, (1945), modified by P.H. GUTH in Gastroenterology, 7 £, 88 (1976).

After 48 hours of fasting, the rats receive the dispersion medium or to be examined "substance by buccal route in a volume of 1 ^cm3 / 100 g.

One hour later, the animals are anesthetized with ether. A longitudinal incision is made approximately 1 cm below of the sternum, exposing the glandular part of the stomach and the duodenum and ligating a few millimeters through below the pylorus. The muscular plane is sutured and the skin is stapled.

An hour later, 200 mg / kg Aspirin _/ dispersed in a suspension of 1% methylcellulose in water, which is mixed with 150 mmol of hydrochloric acid, g administered by oral route in a volume of 0.5 ^cm3 / 100.

Two hours after this last administration, the animals are sacrificed with carbon dioxide.

Before the stomach is removed, a ligature is placed above the cardia.

The gastric fluid is collected to measure the pH of the treated animals and the control animals.

The following results are obtained:

η ο «« ■ * «■

- 19 -

Product of
example dose
(mg / kg) gastric fluid pH 2.0
1.8
2.3
2.3
2.4
^V 2, l
2.4 7th
7th
7th
B.
. 8th
8th
8th 100
20th
4th
100
20th
* 4
0.8 treated comparative
Animals ι animals 4.1
2.4
2
4.6
3
2.2
2.3

3 » Determination of acute toxicity

The lethal dose LD _{50 of} the derivatives of Examples 1 to 9 was determined after administration by the oral route to mice.

The following results were obtained:

Product of example LD ₅₀ (mg / kg) 1 1000 2 '600 3 1000 4th 600 5 200 7th > 400 8th ^ ■ 400 9 ViQQ

Claims (11)

Claims wherein the three methoxy radicals in 3,4,5- or 2,4,6- or 2,4,5- or 2,3,5- or 2,3,6-position, in which either A and B together represent a double bond or A represents a hydrogen atom and B represents a hydroxy radical and wherein R represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms in the various possible stereoisomeric forms and the alkali metal, alkaline earth metal or amine salts of the products of the formula I in which R is hydrogen atom means. 2. The products of formula I according to claim 1, wherein A and B together represent a double bond in the form of the E or Z isomers and the alkali, alkaline earth or amine salts thereof Products of the formula I in which R is a hydrogen atom. 3. The products of formula I according to claim 1, wherein A and B together represent a double bond in the form of the E isomers and the alkali, alkaline earth or amine salts thereof Products of the formula I in which R is a hydrogen atom. 4. The products of formula I according to claim 1, wherein the three Methoxy radicals are present in the 3,4,5- or 2,4,5-position, in the form : Γ;: \ · :: - ·· ': 32UQ82 the Ε isomers and the alkali, alkaline earth or amine salts of these products of the formula I in which R is a hydrogen atom . 5. The (E) -4- (3,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid. 6. The (E) ~ 4- (2,4,5-trimethoxyphenyl) -4-oxo-2-butenoic acid. 7. Process for the preparation of the products of the formula I according to Claim 1 in the various possible stereoisomers Forms and the alkali, alkaline earth and amine salts of these products of the formula I, in which R is a hydrogen atom, characterized in that the glyoxylic acid or one of its alkyl esters of the formula II OHC-COOR (II) wherein R is a hydrogen atom or an alkyl radical having 1 to 5 carbon atoms, with an acetophenone of the formula III (III) wherein the methoxy radicals occupy the positions indicated in claim 1, converted to a product of the formula I _A corresponding to a product of the formula I in which A is a hydrogen atom and B is a hydroxy radical, or a product of the formula I_ corresponding to a product of Formula I, in which A and B together form a double bond with a Ε configuration, and optionally a Product of formula I. Subjected to a dehydrating agent to give a corresponding product of formula I, with E-Kohfiguration and, if desired, at one obtained product of the formula I _A cleavage in his "" 3 - makes optically active isomers and, if desired, a compound of the formula I with Ε _{configuration isomerically converted into a compound of the formula I 13} with Z configuration and, if desired, a product of the formula I in which R is a hydrogen atom, according to customary methods Salt transferred or esterified. 8. As medicaments, the products of the formula I according to any one of claims 1 to 4 in the various stereoisomeric forms, and the pharmaceutically acceptable alkali, alkaline earth or amine salts of these products of the formula I, in which R means a hydrogen atom. 9. As a medicament, a product according to claim 3. 10. As a medicament, the product according to claim 6. 11. Pharmaceutical compositions, characterized in that they as active ingredient at least one of the medicaments according to any one of claims 8 to 10 included.